rs776187492

Variant names:

• chr2-151591368-A-T
• rs776187492
• NM_001164507.2:c.14914T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164508.2(NEB):​c.14914T>A​(p.Ser4972Thr) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0015 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.61
• Publications: 1 publications found

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010239273).
• BP6: Variant 2-151591368-A-T is Benign according to our data. Variant chr2-151591368-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.14914T>A	p.Ser4972Thr	missense	Exon 96 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.14914T>A	p.Ser4972Thr	missense	Exon 96 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.14914T>A	p.Ser4972Thr	missense	Exon 96 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.14914T>A	p.Ser4972Thr	missense	Exon 96 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.14914T>A	p.Ser4972Thr	missense	Exon 96 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11602-15014T>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152152 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00326

Gnomad SAS AF: 0.0214

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00351 AC: 555 AN: 158268 AF XY: 0.00457

Gnomad AFR exome AF: 0.00195

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00557

Gnomad FIN exome AF: 0.000177

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00224

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00147 AC: 2048 AN: 1397180 Hom.: 11 Cov.: 33 AF XY: 0.00197 AC XY: 1357 AN XY: 689042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00114 AC: 36 AN: 31500

American (AMR) AF: 0.000112 AC: 4 AN: 35746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00246 AC: 88 AN: 35740

South Asian (SAS) AF: 0.0192 AC: 1513 AN: 78780

European-Finnish (FIN) AF: 0.000344 AC: 17 AN: 49406

Middle Eastern (MID) AF: 0.000732 AC: 3 AN: 4100

European-Non Finnish (NFE) AF: 0.000239 AC: 258 AN: 1078858

Other (OTH) AF: 0.00223 AC: 129 AN: 57870

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00137 AC: 208 AN: 152270 Hom.: 0 Cov.: 30 AF XY: 0.00168 AC XY: 125 AN XY: 74434

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00159 AC: 66 AN: 41500

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00327 AC: 17 AN: 5196

South Asian (SAS) AF: 0.0214 AC: 103 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68040

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00106 Hom.: 0

ExAC AF: 0.00262 AC: 185

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.010	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.64	T
PhyloP100		6.6
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.16
Sift	Benign	0.33	T
Sift4G	Pathogenic	0.0	D
Vest4		0.46
MutPred		0.43		Loss of disorder (P = 0.0986)
MVP		0.67
MPC		0.21
ClinPred		0.025	T
GERP RS		3.2
gMVP		0.0052
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776187492; hg19: chr2-152447882;